Process for the preparation of 7-chloro-benzodiazepine derivatives

ABSTRACT

Process for the preparation of 7-Cl benzodiazepine derivatives comprised in the general formula   WHEREIN R H, CH3, R1 H, OH, OCOCH3 and the ring B may be substituted or unsubstituted, characterized in that a benzodiazepine of the formula   WHEREIN R, R1 and B have the above indicated meanings, is chlorinated with elemental chlorine in the presence of nitrobenzene as the solvent.

ilnite States Patent [191 Ziggiotti et al.

[ Dec. 3, 1974 Italy [73] Assignee: Ravizza S.A., Lausanne, Switzerland [22] Filed: Mar. 1, 1972 [21] Appl. No.: 230,994

[30] Foreign Application Priority Data Mar. 5, 1971 Great Britain 6140/7l [52] US. Cl. 260/2393 D, 260/999 [51] Int. Cl C07d 53/06 [58] Field of Search 260/2393 D, 570 AB [56] References Cited UNITED STATES PATENTS 3,635,948 l/l972 Ning et al 260/239 BD Primary Examiner-Henry R. Jiles Assistant ExaminerRobert T. Bond Attorney, Agent, or Firm-Stevens, Davis, Miller & Mosher [57] ABSTRACT Process for the preparation of 7-Cl benzodia zepine derivatives comprised in the general formula wherein R H, (EH R H, on, ococn and the ring B may be substituted or unsubstituted, characterized in. that a benzodiazepine of the formula wherein R, R and B have the aboveTndicated meanings, is chlorinated with elemental chlorine in the presence of nitrobenzene as the solvent 1 Claim, No Drawings 1 2 PROCESS FOR THE PREPARATION OF and after two hours the precipitation of a crystalline 7-CHLORO-BENZODIAZEPINE DERIVATIVES product commenced. The mixture was stirred for a further 24 hours in the dark, and then 30 ml of diethyl This invention relates to a process for the preparation ether were added and the resulting precipitate was filof 7-chloro-benzodiazepine derivatives. 5 tered.

It is known that-benzodiazepines constitute a class of Th i it t w suspended i 20 ml of a tic acid highly interesting compounds h h h found Wide and the mineral acid was neutralized with sodium aceuse in the fi ld f psycodrugs. art cu a ly g d results tate. Then water was added little by little up to incipihave been obtained with 7-chloro-d1azep1ne derivatives m lli ti th mixture was left at rest for 1 of the general formula: 10 hour and the resulting precipitate was filtered and washed with water. /NO=O 1.1 g of 7-chloro-3-acetoxy-5-phenyl-l,4-benzodiazepine-2-( ll-l)-one were obtained showing a melting point of 248 to 250 C. Nearly all the unconverted 1 starting material was recovered from the mother liquors.

B l EXAMPLE 2 10 g of l,3-dihydro-5-phenyl-l,4-benzodiazepine- 2-one were suspended in 70 ml of nitrobenzene and 3.2

wherein R represents a hydrogen atom or a methyl radical and R represents a hydrogen atom or a hydroxy or acetoxy radical.

These compounds have hitherto been prepared from starting materials already containing a chlorine atom at the appropriate position in a ring A.

This invention provides a process for the preparation of 7-chloro-benzodiazepine derivatives of the general g of chlorine were dissolved therein while maintaining the temperature not higher than 20 C.

The mixture was stirred in the dark for 48 hours. The product that separated was suspended in 100 ml of water and 100 ml of diethyl ether and neutralized with sodium bicarbonate whilst stirring. I

After crystallization from 70 percent ethyl alcohol 5.5 g of 7-chloro-5-phenyl 3l-l-l ,4-benzodiazepine-2- formula: R (ll-l)-one were obtained, M.P. 215 C. All the unconl verted starting material was recovered from the mother N C=O liquors.

CH Rl We claim: 1. A process for the preparation of a 7-chlorol;= benzodiazepine-2-one of the formula R I l-0:0 B l oH-Rl wherein R and R are as above described and the ring 40 CF B is substituted or unsubstituted, wherein a solution of l benzodiazepine having the formula:

R l l b-(1:0

I CH R1 wherein R H, CH R, H, OH, OCOCH characterized in that a benzodiazepine of the formula C=N f I NC=O B l wherein R, R andm above indicated meanings in nitrobenzene is reacted with elemental chlorine.

The following Examples illustrate the invention.

EXAMPLE 1 wherein R and R have the above indicated meanings, 2.9 g of S-acetoxy-S-phenyl-l,4-benzodiazepine-2- is chlorinated with elemental chlorine (ll-l)-one were suspended in 30 ml of nitrobenzene and 0 in the presence of nitrobenzene as the solvent at a whilst stirring 0.8 g of gaseous chlorine was dissolved temperature of not higher than 20 C.

therein. After a few minutes a clear solution formed 

1. A PROCESS FOR THE PREPARATION OF A 7-CHLOROBENZODIAZEPINE-2-ONE OF THE FORMULA 